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Establishment of curative therapy for Alzheimer's disease with Humanin peptides

护脑肽治疗阿尔茨海默病的建立

基本信息

批准号：
16590088
负责人：
HASHIMOTO Yuichi
金额：
$ 2.3万
依托单位：
KEIO University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590088/
关键词：
Alzheimer's disease neuronal cell death Humanin STAT3 amyloid precursor protein transforming growth factor β2 シグナル伝達アミロイドβペプチド APP プレセニリン p75ニューロトロフィン受容体 PLAIDD

项目摘要

In this research term, we found and reported that the mechanism of Humanin (HN) neuroprotective activity against Alzheimer's disease (AD)-relevant indults and the novel AD-relevant neuronal cell death mechanisms, especially we found the natural and neuronal cell death inducible ligand for amyloid precursor protein (APP).1.The mechanisms of HN neuroprotectionIn 2001, we found HN which is consisted of 24 amino acids, and inhibited neuronal cell death by AD-relevant insults such as familial AD (FAD)-linked APP mutants, presenilin-1 (PS1) mutants, PS2 mutants, neurotoxic amyloid-β peptides. It is not fully understood the HN neuroprotective functions. We succeeded HN-derivatives which have no neuroprotective activity but have its self-dimerization activity. So, these derivatives (P3A, L12A, S14A, and P19A) can act as HN antagonists.Until now, genetistein, a typical tyrosine kinase inhibitor, inhibited HN activity against V642I-APP-induced F11 neurohybrid cell death. Therefore, we used vario … More us kinase inhibitors and mutant genes which can act as dominant negative forms. We identified the involvement of signal transducer and transcription 3 (STAT3) in HN neuroprotective activity against AD-relevant insults induced neuronal cell death. These indicated that the putative receptor complex for HN is upstreams of STAT3 and related to certain tyrosine kinases. These results are important for the identification of HN receptor complex and small compound which can mimic HN action.2.The molecular mechanisms of AD-relevant neuronal cell deathUntil now, we found and reported that 22C11, a monoclonal antibody developed against extracellular domain of APP, can induce neuronal cell death. In addition, we reported that pertussis toxin (PTX) sensitive Go protein, Gβγ proteins, c-Jun N-terminal kinase, NADPH oxidase, and caspase-3/related caspase are involved in the neuronal cell death. By various binding experiments and cell death experiments, we found that transforming growth factor β2 (TGFβ2) binds to the extracellular domain of APP and induce the neuronal cell death via APP in PTX sensitive manner. In addition, we reported that the protein expression of TGFβ2 in cortex M1 region of 18-months-old female Tg2576 Alzheimer's disease model mouse. From these results, there is a possibility that TGFb2 is involved in the onset of AD.The p75 neurotrophin receptor (p75NTR) is a candidate for Aβ receptor which can cause neuronal cell death. In 2002, PLAIDD molecule has been identified by Frankowski et al., and is similar to p75NTR. Therefore, we attempted to investigated the involvement of PLAIDD in Aβ/p75NTR-induced neuronal cell death. From the results, we concluded that PTX sensitive Gi proteins bind to the intracellular domain of PLAIDD and Aβ/p75NTR/PLAIDD can trigger the neuronal cell death as same as Aβ/p75NTR. Less

在本研究中，我们发现并报道了人蛋白(HN)对阿尔茨海默病(AD)相关神经保护作用的机制以及与AD相关的神经细胞死亡机制，特别是我们发现了淀粉样前体蛋白(APP)的天然和神经细胞死亡诱导配体。1.HN的神经保护机制2001年，我们发现了由24个氨基酸组成的HN，并通过家族性AD(FAD)连锁APP突变体、早老素-1(PS1)突变体、PS2突变体、神经毒性淀粉样蛋白-β多肽等抑制AD相关的神经细胞死亡。HN的神经保护作用尚不完全清楚。我们成功地合成了不具有神经保护活性但具有自二聚活性的HN-衍生物。因此，这些衍生物(P3A、L12A、S14A和P19A)可以作为HN的拮抗剂。到目前为止，典型的酪氨酸激酶抑制剂gentistein可以抑制HN的活性，对抗V642I-APP诱导的F11神经杂交细胞死亡。因此，我们使用了VARIO…更多可以作为显性阴性形式的美国激酶抑制物和突变基因。我们发现信号转导和转录3(STAT3)参与了HN对AD相关损伤诱导的神经细胞死亡的神经保护作用。提示HN的受体复合体可能是STAT3的上游，与某些酪氨酸激酶有关。这些结果对鉴定HN受体复合体和模拟HN作用的小分子化合物具有重要意义。2.AD相关神经细胞死亡的分子机制目前，我们发现并报道了抗APP胞外区的单抗22C11可以诱导神经细胞死亡。此外，我们还报道了百日咳毒素敏感的GO蛋白、G-βγ蛋白、c-jun氨基末端激酶、NADPH氧化酶和caspase-3/相关的caspase参与了神经细胞的死亡。通过各种结合实验和细胞死亡实验，我们发现转化生长因子β-2(转化生长因子-β-2)与APP的胞外区结合，以PTX敏感的方式通过APP诱导神经细胞死亡。此外，我们还报道了18月龄雌性Tg2576阿尔茨海默病模型小鼠大脑皮质M1区转化生长因子β-2的蛋白表达。P75神经营养素受体(P75NTR)是Aβ受体的候选受体，可导致神经细胞死亡。PLAIDD分子于2002年由Frankowski等人鉴定，与p75NTR相似。因此，我们试图探讨PLAIDD在Aβ/p75NTR诱导的神经细胞死亡中的作用。结果表明，PTX敏感的GI蛋白与PLAIDD的胞内结构域结合，Aβ/p75NTR/PLAIDD与Aβ/p75NTR一样可引起神经细胞死亡。较少

项目成果

期刊论文数量（34）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Involvement of tyrosine kinases and STAT3 in Humanin-mediated neuroprotection

DOI：
10.1016/j.lfs.2005.03.031
发表时间：
2005-10-28
期刊：
LIFE SCIENCES
影响因子：
6.1
作者：
Hashimoto, Y;Suzuki, H;Matsuoka, M
通讯作者：
Matsuoka, M

Molecular characterization of neuronal cell death by Alzheimer's amyloid-β peptides via p75NTR/PLAIDD.

通过 p75NTR/PLAIDD 对阿尔茨海默病淀粉样蛋白-β 肽引起的神经细胞死亡进行分子表征。

DOI：
发表时间：
2004
期刊：
J.Neurochem. 90(3)
影响因子：
0
作者：
Hashimoto Y.;et al.
通讯作者：
et al.

Involvement of tyrosine kinases and STAT3 in Humanin-mediate neuroprotection

酪氨酸激酶和 STAT3 参与人源介导的神经保护

DOI：
发表时间：
2005
期刊：
Life Sciences 77
影响因子：
0
作者：
I.Nakanishi;T.Kawashima;K.Ohkubo.;H.Kanazawa.;K.Inami.;M.Mochizuki.;K.Fukuhara.;H.Okuda.;T.Ozawa;S.Itoh.;S.Fukuzumi.;N.Ikota;Feril LB et al.(4^ author in 9 authors);Yuichi Hashimoto
通讯作者：
Yuichi Hashimoto

Molecular characterization of neuronal cell death by Alzheimer's a myloid-β peptides via p75NTR/PLADD

阿尔茨海默病 a myloid-β 肽通过 p75NTR/PLADD 对神经元细胞死亡的分子表征

DOI：
发表时间：
2004
期刊：
Journal of Neurochemistry 90
影响因子：
0
作者：
S.Miyake;K.Anzai;N.Ikota;T.Ozawa;M.Toyoda;S.Sato;M-C-i Lee;et al.;K.Watanabe et al.;Hashimoto Y.;Kitamura et al.分担(R.C.Gupta編集);Hashimoto Y.
通讯作者：
Hashimoto Y.

Humanin antagonists: mutants that interfere with dimerization inhibit neuroprotection by Humanin